The ultimate goal of this Fast Track Phase I/II SBIR proposal is to perform the clinical assessment of a novel pharmaceutical agent, ioflubenzamide I-131, to evaluate its potential as a molecular targeting radio-therapeutic treatment for metastatic melanoma. Preliminary results in melanin expressing cell cultures, demonstrate high and selective binding to melanoma cancers. Organ distribution studies in mouse tumor models showed high accumulation in tumors and rapid elimination through the renal and hepatobillary systems. Early human testing, of a similar compound in this series, also demonstrated high uptake and retention in tumors of metastatic melanoma patients. However, process development studies of this earlier lead compound indicated it was too unstable to scale up to high radioactive concentrations. Ioflubenzamide I-131 is a radio-iodinated benzamide molecule with extremely high selective binding to melanin expressing melanomas and low non-target organ accumulation. The molecular target specificity, high tumor accumulation and retention are ideal properties for an agent to effectively treat melanoma metastasis. Preliminary preclinical efficacy studies demonstrated complete tumor remission after two treatments (0.68 mCi) with ioflubenzamide I-131 in a SK-Mel-3 human melanoma xenograft mouse model (about 100 mCi/m2 as a human dose equivalent). The first six month phase of this proposal will focus on generating CMC documentation necessary to support an exploratory IND application to the FDA. The second phase of the proposal will be initiated after the protocol has been accepted by the FDA. This 18 month phase 2 portion will focus on executing and completing a clinical imaging study in 12 (male and female) subjects with confirmed metastatic malignant melanoma to determine safety and organ dosimetry. The justification for requesting Fast Track consideration is to establish the proof-of-principal and select a therapeutic starting dose for a therapy escalation study. The innovation in this proposal is the exciting promise for a potential curative treatment of metastatic melanoma. Following successful completion of the SBIR program, Molecular Insight will develop a clinic protocol to determine dosage and efficacy for an industry sponsored NDA to the FDA. PUBLIC HEALTH RELEVANCE: The incidence of malignant melanoma is rising faster than that of any other types of cancer in the United States. A radiopharmaceutical, capable of being labeled with cell destroying radioisotopes and exclusively targeted to melanoma tissue, would provide a drug specific for the treatment of metastatic disease. The successful development of an I-131 labeled molecular targeting radiotherapeutic agent for malignant melanoma would introduce this therapeutic technique to a now incurable disease and bring considerable attention to the field of therapeutic radiology. Molecular Insights desires to test a new molecular targeting agent: ioflubenzamide I-131 in subjects with confirmed melanin positive metastatic melanomas, to determine its potential as a systemic radiotherapy agent. The rising incidence of malignant melanomas, the early and wide-spread occurrence of metastases, and the poor response rates for current therapies, creates an essential need and valuable commercial opportunity to effectively treat patients with metastatic melanomas.